The invention generally relates to novel chiral aminoalcohol catalysts. The first is prepared by selectively hydrogenating one of two benzene rings in a precursor. The second is by selective dialkylation of a 3-exo-aminoisoborneol with a 2-haloethyl ether. In both cases, the aminoalcohol promotes the asymmetric addition of organozinc reagents to aldehydes to yield optically active alcohols or their esters.
Modem organic chemists have as one goal the development of new synthetic routes for the controlled, efficient production of asymmetric compounds. Saturated carbon atoms, constituting the backbones of most organic compounds, are attached to adjacent atoms through a tetrahedral arrangement of chemical bonds. If the four bonds are to different atoms or groups, the central carbon provides a chiral, or asymmetric, center and the compound therefore may have the ability to exist in two mirror image, or enantiomeric, forms. It is crucial when synthetic organic chemists attempt to prepare these asymmetric compounds to have a means to produce the desired enantiomer because compounds of the wrong enantiomeric form often lack desirable biological, physical or chemical properties.
A particularly attractive approach to the synthesis of optically active compounds is the catalytic asymmetric generation of carbon-carbon bonds. This approach is highly efficient because the optical activity is installed during the assembly of the carbon skeleton rather than as a separate, subsequent operation. Among such reactions the enantioselective addition of organometallic reagents to aldehydes has received much attention in the literature. This transformation represents the enantioselective version of the venerable Grignard addition and affords broadly useful, optically active secondary alcohols as products. Organozinc reagents are usually employed as the organometallic reactant since they do not react with aldehydes in the absence of a catalyst.
General reviews cite the use of optically active xcex2-aminoalcohols to catalyze the asymmetric addition of organozinc reagents to aldehydes (Noyori, R., Kitamura, M., Angew. Chem., Int. Ed. Engl. 1991, 30, 49; Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833). Among such catalysts, the best known and most widely used appears to be 3-exo-(dimethylamino)isoborneol, more commonly known as DAIB (Kitamura, M. et al., J. Am. Chem. Soc. 1986, 108, 6071). DAIB allows highly selective addition of organozinc reagents to certain aldehydes, especially aryl derivatives. However, DAIB requires an expensive and complex 6-step synthesis and is not suitable for addition of organozinc reagents to sterically encumbered aldehydes such as pivalaldehyde. Other aminoalcohols such as N,N-dibutylnorephedrine or DBNE (Soai, K. et al., J. Org. Chem. 1991, 56, 4264) are easier to prepare but are less selective catalysts than DAIB.
Clearly, a need exists for an improved catalyst for the asymmetric addition of organozinc reagents to aldehydes which is both readily synthesized and provides high selectivity with a wide range of aldehyde substrates. The present invention provides an improved process for the synthesis of compounds in a desired enantiomeric form. Other objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description, which hereinafter follows.
The present invention provides for an erythro-xcex2-aminoalcohol compound of Formula 1. The compound is preferably optically active. 
The invention also provides for a process to prepare an erythro-xcex2-aminoalcohol compound of Formula 1 comprising selectively hydrogenating an erythro-xcex2-aminoalcohol of Formula 2 to form the erythro-xcex2-aminoalcohol of Formula 1. 
The hydrogenation is preferably performed in the presence of a catalyst comprising rhodium supported on an inorganic support. More preferably, the catalyst is 5% rhodium on alumina. A preferred form of the process is where the erythro-xcex2-aminoalcohol compound of Formula 1 is optically active. Also preferred is where xcex2-aminoalcohol of Formula 2 is prepared by reacting stilbene oxide with morpholine.
Another aspect of the invention provides for a process to prepare a compound of the Formula 6: 
comprising: a) contacting an aldehyde of formula RC(O)H with a zinc compound of formula Rxe2x80x2ZnRxe2x80x3 in the presence of a catalytic amount of an erythro-xcex2-amino-alcohol of Formula 1; b) further contacting the reactants with Y2O to form the corresponding ester or alcohol of Formula 6 wherein R, Rxe2x80x2, and Rxe2x80x3 are hydrocarbyl or substituted hydrocarbyl; Y is a hydrogen or alkanoyl group; and Y2O is a carboxylic acid anhydride or water.
A preferred process is where the erythro-xcex2-aminoalcohol and the compound of Formula 6 are optically active. More preferred is where the compound of Formula 6 has an enantiomeric excess of greater than about 80%, and most preferred is where the compound of Formula 6 has a high level of enantiomeric purity.
Another preferred process is where Y is hydrogen or acetyl. More preferred is where R is selected from the group consisting of phenyl, n-hexyl, 3-thienyl, cyclohexyl, 1,1-dimethyl-3-butenyl, isopropyl, 1-butenyl and isobutyl; and Rxe2x80x2 is selected from the group consisting of ethyl, methyl and 5-chloropentenyl.
The present invention consists of a morpholine-substituted erythro-xcex2-aminoalcohol compound comprising one of the compounds of Formula 1
and a process for their preparation.
The following definitions are used herein:
The term xe2x80x9calkanoylxe2x80x9d means a monovalent radical of the formula xe2x80x94C(O)Rxe2x80x3, where Rxe2x80x3 is hydrogen, hydrocarbyl or substituted hydrocarbyl group.
The term xe2x80x9ccarboxylic acid anhydridexe2x80x9d means a compound containing the grouping xe2x80x94C(O)O(O)Cxe2x80x94, wherein the free valencies are to other carbon atoms.
The term xe2x80x9cchiralxe2x80x9d means xe2x80x9cexisting as a pair of enantiomersxe2x80x9d. These stereoisomers, designated the R and S enantiomers, are mirror images of one another. A chiral material may either contain an equal amount of the R and S isomers (in which case it is called xe2x80x9cracemicxe2x80x9d) or it may contain inequivalent amounts of R and S isomer (in which case it is called xe2x80x9coptically activexe2x80x9d). The extent of this inequivalence is measured as the xe2x80x9cenantiomeric excessxe2x80x9d.
When two chiral centers exist in one molecule, there can be up to four different stereoisomers. In such a molecule, if the two centers have one substituent in common, they can be further characterized as xe2x80x9cerythroxe2x80x9d or xe2x80x9cthreoxe2x80x9d. When the two identical substituents are on the same side when drawn in the standard Fischer convention, the molecule is labeled erythro. (For a further discussion, see Advanced Organic Chemistry, 2nd edition, J. March, Ed., 1977, pp 104-106.)
The term xe2x80x9cenantiomeric excessxe2x80x9d means the difference between the percent of R enantiomer and the percent of S enantiomer of an optically active compound. For example, a compound that contains 75% S isomer and 25% R isomer will have an enantiomeric excess of 50%.
The term xe2x80x9chigh level of enantiomeric purityxe2x80x9d means having an enantiomeric excess of greater than or equal to about 90%, preferably greater than or equal to about 95%.
The term xe2x80x9cenantioselectivexe2x80x9d means having the ability to produce a product in an optically active form.
By the term xe2x80x9chydrocarbylxe2x80x9d Applicant includes all alkyl, aryl, aralkyl or alkylaryl carbon substituents, either straight chain, branched or cyclic. xe2x80x9cSubstituted hydrocarbylxe2x80x9d means a hydrocarbyl group containing a substituent such as, but not limited to, halide or oxygen functionalities such as, but not limited to, ether, ester, and acetal.
A preferred form of the invention is a morpholine-substituted xcex2-amino-alcohol compound that is optically active.
Applicant has further discovered that the aminoalcohol of Formula 1 is an enantioselective catalyst for the addition of organozinc reagents to many aldehydes, including sterically hindered aldehydes, to produce optically active secondary alcohols or their ester derivatives. Optically active alcohols and esters are important intermediates for the manufacture of many biologically active compounds. One such reaction is the preparation of enantiopure succinate derivatives, which are components of matrix metalloproteinase inhibitors.
Another aspect of the invention is a process for the preparation of the morpholine-substituted erythro-xcex2-aminoalcohol of Formula 1 comprising selectively hydrogenating the morpholine-substituted erythro-xcex2-aminoalcohol of Formula 2 to form the morpholine-substituted xcex2-aminoalcohol of Formula 1 in the presence of a catalytic amount of Rh supported on a inorganic support. 
A preferred aspect of this invention is a process to prepare the morpholine-substituted erythro-xcex2-aminoalcohol of Formula 1 in an optically active form. Either the (1R, 2S) or (1S, 2R) enantiomer of Formula 1 can be prepared, depending on which enantiomer of 2 is used as starting material.
Any procedure known in the art can be used to prepare the morpholine-substituted erythro-xcex2-aminoalcohol of Formula 2 that is used as the starting material. One such procedure uses stilbene oxide as a precursor and comprises reacting (R, R)- or (S, S)-stilbene oxide with morpholine to prepare the corresponding (1R, 2S)- or (1S, 2R)-morpholine-substituted xcex2-aminoalcohol of Formula 2, at a temperature of 50xc2x0 C. to 200xc2x0 C., either in an inert solvent with suitable boiling point or, preferably, in the absence of solvent. Another procedure is described in Xi, C. et al., J. Am. Chem. Soc. 1991, 113, 3893.
A preferred aspect of this invention is a process to prepare the morpholine-substituted xcex2-aminoalcohol of Formula 2 in an optically active form. This is done by using an optically active form of stilbene oxide as a starting material.
The hydrogenation is performed in the presence of a catalyst that consists of rhodium supported on an inorganic support. Suitable supports include, but are not limited to alumina, silica and titania, and the loading of rhodium can be from 0.5% to 20%. Most preferably, the catalyst is 5% rhodium on alumina.
The hydrogen pressure can be about 10 to 1000 atmospheres (1 to 100 MPa) with about 50 to 200 atmospheres (5 to 20 MPa) most preferred.
The hydrogenation reaction is carried out in a protic solvent, preferably an alcohol. Suitable solvents include, but are not limited to methanol, ethanol, isopropanol, n-propanol, or t-butyl alcohol.
In order to provide the necessary acidic environment, an acidic additive is present in a molar amount greater than the amount of aminoalcohol 2 in the system. Examples of acidic additives include, but are not limited to, hydrochloric acid, phosphoric acid, formic acid, propionic acid, or acetic acid. Organic carboxylic acids are preferred and acetic acid is most preferred.
The hydrogenation is carried out between 0xc2x0 C. and 200xc2x0 C., preferably between 25xc2x0 C. and 100xc2x0 C.
The invention further includes a method for the preparation of alcohol or esters using 1 as a catalyst. The general scheme can be pictured as follows: 
The reaction comprises: a) contacting an aldehyde of formula RC(O)H with a zinc compound of formula Rxe2x80x2ZnRxe2x80x3 in the presence of a catalytic amount of an aminoalcohol of Formula 1; b) further contacting the reactants with Y2O to form the corresponding ester or alcohol of Formula 6; wherein R, Rxe2x80x2, and Rxe2x80x3 are hydrocarbyl or substituted hydrocarbyl; Y is hydrogen or a alkanoyl group; and Y2O is a carboxylic acid anhydride or water.
Preferred processes are where the aminoalcohol 1 and the compound of Formula 6 are optically active. The catalyst enantiomer chosen determines which enantiomer of the product is prepared. More preferred is where the compound of Formula 6 has an enantiomeric excess of greater than about 80%. Most preferred is where the compound of Formula 6 has a high level of enantiomeric purity.
Also preferred is where Y is hydrogen or acetyl and where R is selected from the group consisting of phenyl, n-hexyl, 3-thienyl, cyclohexyl, 1,1-dimethyl-3-butenyl, isopropyl, cyclopropyl, 1-butenyl, and isobutyl, and Rxe2x80x2 is selected from the group consisting of ethyl, methyl, and 5-chloropentenyl.
The reaction is carried out in a solvent which is aprotic and, preferably, apolar, and which is inert to all reagents and products. Examples of suitable solvents include, but are not limited to, carbon tetrachloride, 1,2-dichloroethane, pentane, hexane, heptane, cyclohexane, benzene, toluene, or mixtures thereof.
The amount of organozinc reagent used relative to aldehyde substrate can be between 1 and 5 molar equivalents, and, preferably about 2 molar equivalents;
The amount of aminoalcohol 1 used as catalyst relative to aldehyde substrate can be between 0.5% and 20%, and, preferably between 2% and 10%.
The temperature can between xe2x88x9225xc2x0 C. and 50xc2x0 C., preferably at between 0xc2x0 C. and 25xc2x0 C. It is, however, most convenient to carry out the reaction at ambient temperature and pressure.
The optically active zinc alkoxide 5 formed in the above reaction may simply be treated with water to release the optically active alcohol 6, Yxe2x95x90H. Alternatively, in certain cases it may be desirable to treat the reaction mixture with one molar equivalent of acetic anhydride to directly convert the product to the corresponding acetate ester 6, Y=acetyl. Both procedures are conveniently carried out at room temperature.
Applicant has also discovered a second aminoalcohol composition A which promotes the addition of organozinc reagents to aldehydes in a highly enantio-selective manner. Aminoalcohol A is prepared by selective dialkylation of 3-exo-aminoisoborneol B with a 2-haloethyl ether. Either enantiomer of A can be prepared, depending on which enantiomer of B is used as starting material. Aminoalcohol A shares a common camphor backbone structure with the known aminoalcohol catalyst DAIB but it differs from DAIB in several unobvious aspects. Thus, DAIB is an air-sensitive liquid which is prepared from B in three steps; in contrast A is an air-stable crystalline solid which is prepared from B in a single step. In addition, A unexpectedly promotes the addition of organozinc reagents to aliphatic aldehydes containing a xcex2-branch (i.e., isobutyraldehyde, cyclohexanecarboxaldehyde) with greatly enhanced enantioselectivity as compared with DAIB.
A general reaction for the preparation of A can be described as follows: 
where
the halide substituent X in the 2-haloethyl ether is chloride, bromide, or iodide; preferably the 2-haloether is 2-bromoethyl ether; the base is a mild organic or inorganic which is compatible with both the primary amine and the halide functional groups and whose basicity is sufficient to deprotonate the unreactive conjugate acid of B when it is protonated by HX. Examples of useful bases include triethylamine, diisopropylethylamine, sodium carbonate and sodium bicarbonate; the solvent is a protic or aprotic organic liquid which is compatible with both the primary amine and haloethyl functional groups and is readily separable from A either by distillation or differential solubility in water. Examples of suitable solvents are dimethylsulfoxide, dimethyl formamide, chlorobenzene, and toluene. Alternatively, the reaction may be run in a two phase system consisting of water and an immiscible organic solvent such as toluene, and optionally in the presence of a phase transfer catalyst; the reaction temperature is between 0xc2x0 C. and 100xc2x0 C. For convenience, the reaction is preferably carried out at room temperature and at atmospheric pressure.
The products of the invention can easily be converted to chiral intermediates useful in the manufacture of pharmaceuticals. Optically-active secondary alcohols 6 can be converted to the ether, ester, carbamate, silyl ether or arenesulfonate functionality without loss of optical activity by methods well known in the art. Moreover, the arenesulfonate derivatives of such secondary alcohols undergo nucleophilic displacement reactions with, for example, azide, cyanide, or thiolate to afford optically active products with inversion of stereochemistry. The optically active ester forms of Formula 6, especially the acetate esters, can be hydrolyzed under either basic or acid conditions to the optically active alcohols.
Although the Applicant contemplates many possible uses for the products of the instant invention, one possible example is use as an intermediate for metalloproteinase inhibitor.
(R,R)-Stilbene oxide and (S,S)-stilbene oxide were prepared using a standard literature procedure (Chang, H.-T., Sharpless, K. B. J. Org. Chem. 1996, 61, 6456). Diethylzinc and dimethylzinc solutions, aldehyde substrates, and all other organic starting materials were purchased from Aldrich Chemical Company, Milwaukee, Wis. The enolizable aldehydes cyclohexanecarboxaldehyde, isobutyraldehyde, and hexanal were distilled immediately prior to use. The Cyclodex B(trademark) capillary GC column used to determine enantiomeric excess was purchased from JandW Scientific, Folsom, Calif.